Drug Interactions between clonidine / ketorolac / ropivacaine and viloxazine

MONITOR: Coadministration with potent inhibitors of CYP450 1A2 may increase the plasma concentrations of ropivacaine, which has been shown to be primarily metabolized by the isoenzyme. In twelve healthy volunteers, pretreatment with the potent CYP450 1A2 inhibitor fluvoxamine (25 mg twice daily for 2 days) increased the mean total plasma clearance of ropivacaine (40 mg IV over 20 minutes) by 68% compared to administration of ropivacaine alone. In eight healthy volunteers, fluvoxamine (100 mg daily for 5 days) increased the area under the plasma concentration-time curve (AUC) of a single dose of ropivacaine (0.6 mg/kg IV over 30 minutes) by 3.7-fold compared to placebo. The ropivacaine AUC was further increased by 50% when fluvoxamine was given in combination with erythromycin (500 mg three times a day), presumably due to the additional inhibition of ropivacaine metabolism via CYP450 3A4. Fluvoxamine alone prolonged the elimination half-life of ropivacaine from 2.3 to 7.4 hours, while the addition of erythromycin further increased the half-life to 11.9 hours.

MANAGEMENT: Clinicians should recognize the potential for increased toxicity of ropivacaine during coadministration with potent CYP450 1A2 inhibitors. The risk may be further increased by concomitant use of CYP450 3A4 inhibitors (e.g., itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, ketolide and certain macrolide antibiotics). Cardiovascular and respiratory vital signs and the patient's state of consciousness should be closely monitored. Restlessness, anxiety, incoherent speech, light-headedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, and drowsiness may be early warning signs of central nervous system toxicity.